Molecular receptors on Group III-IV sensory neurons detecting muscle metabolites Fatigue due to chronic heart failure, chronic obstructive pulmonary disorder (COPD), and other chronic fatiguing disorders is serious, debilitating, and creates poor prognoses for long-term outcomes in these patients. Many more patients are affected by idiopathic, injury, or disease-caused short-term fatigue and myalgia that sometimes remits with treatment or for unknown reasons becomes chronic. Considerable evidence indicates that peripheral sensory dysregulation of group III/IV muscle afferents, and autonomic dysregulation may cause or contribute to the excessive fatigue of chronic heart failure. Our long-term goal is to determine the fundamental mechanisms that signal fatigue to sensory and motor systems, and determine the mechanisms that cause enhanced fatigue in diseases such as heart failure and COPD. In the next three years, we propose a comprehensive evaluation of the molecular receptors on group III/IV muscle afferent neurons that endow these specialized endings with the ability to detect and signal the increases in muscle metabolites that occur with muscle contraction and exercise. Experiments proposed here will use: 1) innovative neuron harvesting and quantitative real-time, PCR (qPCR) to determine which molecular receptors are expressed selectively in group III/IV afferent neurons. 2) calcium imaging, cell harvesting and qPCR to determine how fatigue-selective neurons selectively encode non-painful levels of metabolites. 3) immunohistochemistry to determine if mRNA expressed is translated protein inserted into membrane. 4) whole-cell recording of metabolite activated currents to determine the function of the molecular receptor proteins; and 5) single unit electrophysiological recording in a nerve muscle preparation to determine which metabolites activate these sensory neurons in situ. The results of these experiments will provide the basic science background for the concept of fatigue as an integrated system with powerful influence on the cardiovascular/autonomic system, the sensory-perceptual experience of fatigue, and motor system inhibition. This concept, and the molecular receptors discovered will lead to rational, targeted effective treatments for the excessive fatigue experienced by heart failure patients, patients with COPD, and other patients suffering from prolonged, unexplained fatigue.